Transcript Ch 3. The drug manufacturing process

The manufacturing process of bio-drugs
 The manufacture of biopharmaceutical substances :
- Most highly regulated and rigorously controlled processes
 To gain a manufacturing license, the producer should prove that not
only the product itself is safe and effective, but all aspects of the
proposed manufacturing process comply with the highest quality
standards
 The bio-drugs approved for medical use should be produced using
the same process by which it is intended to undertake pre-clinical
and clinical trials :
 Best manufacturing process (Bioprocess) should be established
 The factors affecting the safe manufacture of quality
bio-drugs
-
Design and layout of the manufacturing facility
Raw materials utilized in the manufacturing process
Manufacturing process itself
Training and commitment of personnel involved
in all aspects of the manufacturing operation
- Existence of a regulatory framework which assures the
establishment and maintenance of the highest quality
standards regarding all aspects of manufacturing
Overview of manufacturing process
 Key elements
- Clean room, Equipment, Personnel, Water,
Documentation (Product standards, protocols, guidelines)
 Infrastructure of a typical manufacturing facility and some
relevant operational issues
 Source of biopharmaceuticals
 Up-stream and down-stream processing of
biopharmaceutical products
 Analysis of the final products : Quality control
International Pharmacopoeia
 Most important factors that determine the safety and efficacy
- Standard of raw materials used in the manufacturing process
- Standard (specification) to which the final product is produced
 Standard processes and guides to good manufacturing practice for
medicinal products : Play a central role in establishing criteria which
guarantee the consistent production of safe and effective bio-drugs
 Most pharmaceutical substances are manufactured to
exacting specifications in publications : Pharmacopoeias
- International Pharmacopoeias
- US (USP), European Pharma ( Eur. Ph.), Japanese Pharmacopoeia
- Products listed in pharmacopoeias : generic drugs
Martindale
 The extra pharmacopoeia
 To provide concise, unbiased information regarding
bio-drugs of clinical interest, largely summarized from
the peer-reviewed literatures : not a book of standards
 First edition published by William Martindale in 1883
- The 30th edition in 1993
 Contains information on around 5,000 bio-drugs in
clinical use: Chemical-based drugs and traditional
biological substances like antibiotics, hormones, and
blood products
 Classified based on similar clinical uses or actions
 Information about
- Physio-chemical characteristics
- Absorption and fate
- Uses and appropriate mode of administration
- Adverse/side effects
- Suitable dosage levels
 List of the major headings under which various drugs
are described in Martindale : Table 3.1
Guides to Good Manufacturing Practice
 All aspects of biopharmaceutical manufacture must
comply with the most rigorous standards to ensure
consistent production of a safe and effective bio-drugs
 Principles underlining such standards are summarized in
publications which detail Good Manufacturing Practice
(GMP)
- EU guide to Good Manufacturing Practice for
Medicinal Products
 Biopharmaceutical manufacturers must be familiar with
the principles, and are legally obliged to ensure adoption
of these principles to their specific manufacturing process
 Regulatory authority assesses compliance of the
manufacturer with the principles by undertaking regular
inspections of the facility
 Subsequent granting/renewing (or refusing) of a
manufacturing license depends largely on the level of
compliance found during the inspection
Principles outlined in GMP
 Each chapter is concerned with a specific aspect of
pharmaceutical manufacture : Common-sense guidelines
- List of contents in the EU Guide to GMP for Medicinal
products : Table 3.2
 GMP in relation to personnel
- Adequate number of sufficiently qualified, experienced personnel
should be employed by the manufacturer
- Key personnel, such as the heads of production and quality control,
must be independent of each other
- Personnel should have well-defined job descriptions, and should
receive adequate training
- Issues of personal hygiene should be emphasized to prevent
product contamination
Principles regarding Premises and equipments
 All premises and equipment should be designed,
operated, and serviced to carry out their intended
functions
 Facility and equipment should be designed and used to
avoid cross-contamination or mix-up between different
products
 Sufficient storage area must be provided, and clear
demarcation must exist between storage zones for
materials at different levels of processing (raw materials,
partially processes products, finished products etc..)
 Quality control labs must be separated from production,
and must be designed to fulfill their intended function
 Some of the principles outlined in the guide are
sufficiently general to render them applicable to most
manufacturing industries
 Most of principles outlined in guides to GMP are equally
as applicable to the manufacture of traditional
pharmaceuticals as to new ones
 Many of the guidelines are specific : Guidelines relating
to the requirement for dedicated facilities when
manufacturing specific products

Manufacturing facility
 Appropriate design and layout of the facility : Crucial to
the production of safe and effective medicines
 Commonly contains :
- Specific production of a target drug
- Quality control, Storage areas, etc
cf) Injectable bio-drugs : Require unique facility design
and operation  safety of product
- Clean room technology
- Generation of ultra pure water (WFI : water for injection)
- Proper design and maintenance of non-critical
areas : storage, labeling, and packing areas
Clean rooms
 Environmentally controlled areas for injectable/sterile
biopharmaceutricals : specifically designed to protect the
product from contamination (microorganisms and
particulate matters etc.)
 Designed in a way that allows tight control of entry of all
substances and personnel (e.g., equipment, in-process
product, air etc..)
 A basic feature of design : Installation of high efficiency
particulate air (HEPA) filters in the ceilings :
- Layers of high-density glass fiber : Depth filter
- Flow pattern of HEPA-filtered air : Fig. 3.1
- Air is pumped into the room via the filters,
generating a constant downward sweeping motion
 Clean rooms with various levels of cleanliness :
- Classified based on the number of airborne particles
and viable microorganisms in the room
- Maximum permitted number of particles or
microorganisms per m3 of clean room air
 Europe :
Grade A :
B:
C:
D:

5 μm particle dia
0
0
2,000
20,000
USA :
class 100 (grade A/B),
class 10,000(grade C),
class 100,000 (grade D)
viable microorganisms
<1
5
100
500
Factors affecting the clean room condition
 Use of HEPA filters with high particulate-removing
efficiency
 Generation of a unidirectional downward air distribution
pattern (i.e. laminar flow)
 Additional elements critical to maintaining intended
clean room conditions
- All exposed surfaces : a smooth, sealed impervious finish in order
to minimize accumulation of dirt/microbial particles to facilitate
effective cleaning procedures
- Floors, walls, and ceilings : coated with durable, chemical-resistance
materials like epoxy resins, polyester, PVC coatings
- Fixtures (work benches, chairs, equipments etc..) :
designed and fabricated to facilitate cleaning processes
- Air-lock systems : buffer zone
- prevention of contamination
- entry of all substances/personnel into a clean room
must occur via air-lock systems
- An interlocking system : doors are never simultaneously
open, precluding formation of a direct corridor between
the uncontrolled area and clean area
 Generalized clean room design: Figure 3.2
- Separated entries and exits for personnel, raw materials,
and products
- Personnel represent a major potential source of process
contaminants: required to wear specialized protective
clothing when working in clean area
- Operators enter the clean area via a separated air-lock
- High standard of personnel hygiene
- Only the minimum number of personnel required should
be present in the clean area at any given time
Cleaning, decontamination, and sanitation (CDS)
 CDS regime : essential to the production of a safe and effective
biopharmaceuticals
- Cleaning : removal of “dirt” (organic/inorganic materials)
- Decontamination : inactivation and removal of undesirable
substances, which generally exhibit some specific biological activity
ex) endotoxins, viruses, prions
- Sanitation : destruction and removal of viable microorganisms
 Effective CDS procedures are routinely applied to :
- Surfaces are not direct contact with the product (e.g. clean room
walls and floors)
- Surfaces coming into direct contact with the product (e.g.
manufacturing vessels, product filters, columns)
 CDS of process equipment
- surfaces/equipment in direct contact with the product : special
CDS requirement
- no trace of the CDS reagents  product contamination
 Final stage of CDS procedures involves exhaustive rinsing with
highly pure water (water for injections (WFI))
 CDS of processing and holding vessels as well as equipment that is
easily detachable/dismantled (e.g., homogenizer, centrifuge rotors
etc.,)  straightforward
 Cleaning in place(CIP) : large equipment/process fixtures
due to the impracticality/undesirability of their
dismantling
ex) internal surfaces of fermentation equipment, fixed
piping, large processing/storage tanks, process-scale
chromatographic column
- General procedure: A detergent solution in WFI,
passage of sterilizing live steam generated from WFI
 CDS of process-scale chromatography systems :
challenging
ex) Processing of product derived from microbial sources :
contamination with lipid, endotoxins, nucleic acids,
proteins
Water for biopharmaceutical processing
 Water : One of the most important raw materials :
 used as a basic ingredient
- Cell culture media, buffers, solvent in extraction and
purification, solvent in preparation of liquid form and
freeze-dried products
- used for ancillary processes : cleaning
- ~ 30,000 liters of water : production of 1 kg of a
recombinant biopharmaceutical produced in a
microbial system
 Generation of water of suitable purity : central to
successful operation of facility
 Two levels of water quality : purified water and WFI
- Outlined in international pharmacopoeias
 Use of purified water:
- Solvent in the manufacture of aqueous-based oral products (e.g.,
cough mixtures, )
- Primary cleaning of some process equipment/clean room floors in class
D or C area,
- Generation of steam in the facilities, autoclaves
- Cell culture media
 Water for injection (WFI)
- Highest purity
- Extensive use in biopharmaceutical manufacturing
Generation of purified water and WFI




Generated from potable water
Potential impurities in potable water : Table 3.7
Multi-step purification steps for purified water and WFI:
Monitoring of each step : continuous measurement of
the resistivity of the water
ex) Deionization : anion/cation exchangers
Increased resistivity with purity up to 1- 10 MΩ
 Filters to remove microorganisms: 0.22 µm, 0,45 µm
 Reverse osmosis (RO) membrane : Semi-permeable
membrane (permeable to the solvent, water, but
impermeable to solute, i.e., contaminants)
General procedure for WFI
Potable water
 depth filtration organic trap (resin)
 activated charcoal
 Anion exchanger Cation exchanger
Deionization step : monitored by measuring the
water resistivity
 Filtration with membrane to remove microorganisms
- “purified water”
 Distillation (or reverse osmosis)
 Water for injection(WFI)
Documentation
 Adequate documentation : Essential part of GMP
 Essential in order to
- Help prevent errors/misunderstandings associated
with verbal communication
- Facilitate the tracing of the manufacturing history of
any batch of product
- Ensure reproducibility in all aspects of pharmaceutical
manufacture
Categories
 Most documents associated with biopharmaceutical
manufacturing fall into one of four categories
- Standard operating procedures (SOPs)
- Specifications
- Manufacturing formulae, processing and
packaging instructions
- Records
 Documents should be written/worded in a clear and
unambiguous fashion by supervisory personnel and
inspected by senior technical personnel like production
or QC manager before final approval for general use
SOPs (Standard Operating Procedures)
 Documents detailing how staff should undertake particular
procedures or processes
 General categories
- SOPs detailing step-by-step operational procedures for specific items
of equipment (e.g., autoclave, homogenizer, freeze-dryers etc.,)
- SOPs detailing maintenance/validation procedures for specific items of
equipment or facility areas, e.g., SOPs detailing CDS of clean rooms
- SOPs relating directly to personnel (e.g., step-by-step procedures
before entering a clean room)
- SOPs relating to testing/analysis (e.g., QC analysis of final product
how to properly sample raw materials/products, testing of WFI etc.)
Specifications
 Exact qualitative and quantitative requirements for raw
materials or product
- Specifications for raw material (ex., percentage active
ingredients, permitted levels of impurities)
- Specifications for packing materials (ex., exact dimension
of product packaging, details of product labels etc.)
- Specifications for final product (ex., purity, color,
formulation etc.)
 Normally written by QC personnel
 Specifications for raw materials / final product :
conforming with appropriate pharmacopoeia
Manufacturing formulae, processing and packaging instructions
 Provide sufficient information to allow a technically
competent person to successfully undertake the
manufacturing procedure
 Manufacturing formulae
- Product name, potency / strength, exact batch size, starting raw
materials, quantity of each material
- Processing instructions :
Principal items of equipment, precise location where each step should
be undertaken (e g., in a specific clean room), specific precautions
during manufacturing, labeling of each product and packing
instructions
 A copy of the label to be used is generally attached to the
documents
Records
 Maintenance of adequate and accurate records
 For any given batch of product, records relating to every
aspect of manufacture are retained for at least 1 year
 Records include:
- Specification results obtained on all raw materials
- Batch manufacturing, processing, and packaging records
- QC analysis results of bulk and finished product
 The records should allow tracing back of all manufacturing
steps, for the case of any difficulty or problem regarding
the production of final product